ABSTRACT Diabetic foot ulcers continue to burden the US healthcare system and patients with an estimated annual cost of $30 billion and amputation rates of 100,000. The exact etiology of the problem remains to be resolved, though it is known to be multi-factorial. Diabetic foot lesions have a biomechanical pathology that involves mechanical stresses acting under the foot; however, foot pressure alone is not a good predictor of ulcers, since ulcers are known to occur at pressure levels that are not considered harmful. Results regarding the pathological effects of plantar shear are not yet conclusive. Preventive footwear, designed to address only peak pressures have shown poor success in preventing ulceration, which further indicates that the pathology is multi-factorial. An alternative theory regarding ulceration states that diabetic peripheral neuropathy leads to unvarying patterns of plantar loading in diabetic patients, which may consequently result in tissue tenderness and breakdown. Healthy individuals have been shown to shift their loading patterns based on sensory feedback, which prevents tissue tenderness and pain at the regional scale. Due to neuropathy, certain regions of the diabetic foot are thought to experience repetitive stresses that are not relieved in response to discomfort or pain that these stresses would create. Prolonged repetition might result in failure of the tissue even with lower, yet unrelieved, mechanical stresses. Developing effective footwear and intervention strategies to prevent diabetic amputations requires a comprehensive approach which addresses multiple causative factors of foot ulceration and allows for the study of these unrelieved repetitive stresses. In this study, we will develop pressure alternating shoes (PAS) that will provide selective rest to the plantar aspect of the foot in order to prevent diabetic ulcers. The ultimate aim of this footwear will be to limit repetition of local plantar stresses, particularly at peak stress sites, and provide tissue an opportunity to recover. This periodic off-loading will also help prevent ischemic conditions in the plantar tissue, particularly in diabetic patients who stand for a long time. We will design and test the PAS to achieve the selective rest function and evaluate its safety, usability, biomechanical characteristics and comfort with healthy and diabetic subjects. This will be the first study on the effect of a device actively modulating the mechanical loading at the plantar surface for foot ulcer prevention and will allow for a systematic study of cyclical mechanical loading effects on foot ulcer formation which will advance understanding in the field of diabetic foot care. Ultimately, such a study has the potential to significantly impact the long term care of diabetics with a high prevalence of foot ulceration and improve their quality of life.